Valosin-containing protein (VCP) belongs to a subfamily of ATPase, AAA (ATPases Associated with diverse cellular Activities), and is highly conserved among species. ATPases belonging to AAA are characterized in that they possess SRH (Second region of homology) region consisting of a similar amino acid sequence as a common structure in their C-terminal, in addition to Walker A motif (WA) which binds to ATP and Walker B motif (WB) which is involved in hydrolysis by the ATPase. The coordinated activity of WA, WB and SRH regions is thought to hydrolyze ATPs. VCP is mainly consisted of four regions, N-terminal region, D1 ATPase (D1) region, D2 ATPase (D2) region and C-terminal region, and possesses two ATPase regions characteristic of AAA family. Among them, D2 ATPase region is considered to be mainly responsible for the ATPase activity. In the two ATPase regions ATPase domain is followed by α-helix-enriched region, each of them is called D1α and D2α domain, respectively. The N-terminal region is known to have a function binding to and recognizing ubiquitin or degenerated proteins, and to be a binding region with cofactors such as Npl4, Ufd1 and p47 (Non-patent Literature 1).
It has been previously reported that VCP is involved in mechanisms of onset of neurodegenerative diseases. One of the mechanisms of onset of neurodegenerative diseases is an excess biological reaction for accumulation and aggregation of abnormal proteins (feedback mechanism). VCP is implied to be involved in such biological reactions. In particular, VCP recognizes and binds to extended polyglutamine observed in the neurodegenerative diseases such as Machado-Joseph disease (MJD) and Huntington's chorea. In addition, it was observed that VCP is co-localized with intranuclear inclusion bodies of MJD or Huntington's chorea, Lewy bodies of Parkinson's disease and aggregations in motor neurons, and recognize and bind to proteins which are believed to be involved in the pathogenesis of several neurodegenerative diseases. Furthermore, VCP is known to be involved in myopathy called IBMPFD (Inclusion Body Myopathy with Paget disease of bone and Front-temporal Dementia), which is dominantly inherited and associated with inclusion bodies after middle age, osteoporosis of Paget type, and diseases associated with frontotemporal dementia. Therefore, VCP is thought to serve not only as a sensor of abnormal proteins, but as an executioner of neuronal death (Non-patent Literature 2).